Authors:Kerstin Wernike; Martin BeerPages: 39 - 60Abstract: Publication date: 2017 Source:Advances in Virus Research, Volume 99 Author(s): Kerstin Wernike, Martin Beer In late 2011, unspecific clinical symptoms such as fever, diarrhea, and decreased milk production were observed in dairy cattle in the Dutch/German border region. After exclusion of classical endemic and emerging viruses by targeted diagnostic systems, blood samples from acutely diseased cows were subjected to metagenomics analysis. An insect-transmitted orthobunyavirus of the Simbu serogroup was identified as the causative agent and named Schmallenberg virus (SBV). It was one of the first detections of the introduction of a novel virus of veterinary importance to Europe using the new technology of next-generation sequencing. The virus was subsequently isolated from identical samples as used for metagenomics analysis in insect and mammalian cell lines and disease symptoms were reproduced in calves experimentally infected with both, this culture-grown virus and blood samples of diseased cattle. Since its emergence, SBV spread very rapidly throughout the European ruminant population causing mild unspecific disease in adult animals, but also premature birth or stillbirth and severe fetal malformation when naive dams were infected during a critical phase of gestation. In the following years, SBV recirculated regularly to a larger extend; in the 2014 and 2016 vector seasons the virus was again repeatedly detected in the blood of adult ruminants, and in the following winter and spring months, a number of malformed calves and lambs was born. The genome of viruses present in viremic adult animals showed a very high sequence stability; in sequences generated between 2012 and 2016, only a few amino acid substitutions in comparison to the initial SBV isolate could be detected. In contrast, a high sequence variability was identified in the aminoterminal part of the glycoprotein Gc-encoding region of viruses present in the brain of malformed newborns. This mutation hotspot is independent of the region or host species from which the samples originated and is potentially involved in immune evasion mechanisms.

Authors:B.W. Neuman; M.J. BuchmeierPages: 1 - 27Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): B.W. Neuman, M.J. Buchmeier Coronavirus particles serve three fundamentally important functions in infection. The virion provides the means to deliver the viral genome across the plasma membrane of a host cell. The virion is also a means of escape for newly synthesized genomes. Lastly, the virion is a durable vessel that protects the genome on its journey between cells. This review summarizes the available X-ray crystallography, NMR, and cryoelectron microscopy structural data for coronavirus structural proteins, and looks at the role of each of the major structural proteins in virus entry and assembly. The potential wider conservation of the nucleoprotein fold identified in the Arteriviridae and Coronaviridae families and a speculative model for the evolution of corona-like virus architecture are discussed.

Authors:R.J.G. Hulswit; C.A.M. de Haan; B.-J. BoschPages: 29 - 57Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): R.J.G. Hulswit, C.A.M. de Haan, B.-J. Bosch Coronaviruses (CoVs) have a remarkable potential to change tropism. This is particularly illustrated over the last 15 years by the emergence of two zoonotic CoVs, the severe acute respiratory syndrome (SARS)- and Middle East respiratory syndrome (MERS)-CoV. Due to their inherent genetic variability, it is inevitable that new cross-species transmission events of these enveloped, positive-stranded RNA viruses will occur. Research into these medical and veterinary important pathogens—sparked by the SARS and MERS outbreaks—revealed important principles of inter- and intraspecies tropism changes. The primary determinant of CoV tropism is the viral spike (S) entry protein. Trimers of the S glycoproteins on the virion surface accommodate binding to a cell surface receptor and fusion of the viral and cellular membrane. Recently, high-resolution structures of two CoV S proteins have been elucidated by single-particle cryo-electron microscopy. Using this new structural insight, we review the changes in the S protein that relate to changes in virus tropism. Different concepts underlie these tropism changes at the cellular, tissue, and host species level, including the promiscuity or adaptability of S proteins to orthologous receptors, alterations in the proteolytic cleavage activation as well as changes in the S protein metastability. A thorough understanding of the key role of the S protein in CoV entry is critical to further our understanding of virus cross-species transmission and pathogenesis and for development of intervention strategies.

Authors:E.J. Snijder; E. Decroly; J. ZiebuhrPages: 59 - 126Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): E.J. Snijder, E. Decroly, J. Ziebuhr Coronaviruses are animal and human pathogens that can cause lethal zoonotic infections like SARS and MERS. They have polycistronic plus-stranded RNA genomes and belong to the order Nidovirales, a diverse group of viruses for which common ancestry was inferred from the common principles underlying their genome organization and expression, and from the conservation of an array of core replicase domains, including key RNA-synthesizing enzymes. Coronavirus genomes (~26–32 kilobases) are the largest RNA genomes known to date and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases. The primary functions that direct coronavirus RNA synthesis and processing reside in nonstructural protein (nsp) 7 to nsp16, which are cleavage products of two large replicase polyproteins translated from the coronavirus genome. Significant progress has now been made regarding their structural and functional characterization, stimulated by technical advances like improved methods for bioinformatics and structural biology, in vitro enzyme characterization, and site-directed mutagenesis of coronavirus genomes. Coronavirus replicase functions include more or less universal activities of plus-stranded RNA viruses, like an RNA polymerase (nsp12) and helicase (nsp13), but also a number of rare or even unique domains involved in mRNA capping (nsp14, nsp16) and fidelity control (nsp14). Several smaller subunits (nsp7–nsp10) act as crucial cofactors of these enzymes and contribute to the emerging “nsp interactome.” Understanding the structure, function, and interactions of the RNA-synthesizing machinery of coronaviruses will be key to rationalizing their evolutionary success and the development of improved control strategies.

Authors:R. Madhugiri; M. Fricke; M. Marz; J. ZiebuhrPages: 127 - 163Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): R. Madhugiri, M. Fricke, M. Marz, J. Ziebuhr Coronaviruses have exceptionally large RNA genomes of approximately 30 kilobases. Genome replication and transcription is mediated by a multisubunit protein complex comprised of more than a dozen virus-encoded proteins. The protein complex is thought to bind specific cis-acting RNA elements primarily located in the 5′- and 3′-terminal genome regions and upstream of the open reading frames located in the 3′-proximal one-third of the genome. Here, we review our current understanding of coronavirus cis-acting RNA elements, focusing on elements required for genome replication and packaging. Recent bioinformatic, biochemical, and genetic studies suggest a previously unknown level of conservation of cis-acting RNA structures among different coronavirus genera and, in some cases, even beyond genus boundaries. Also, there is increasing evidence to suggest that individual cis-acting elements may be part of higher-order RNA structures involving long-range and dynamic RNA–RNA interactions between RNA structural elements separated by thousands of nucleotides in the viral genome. We discuss the structural and functional features of these cis-acting RNA elements and their specific functions in coronavirus RNA synthesis.

Authors:K. Nakagawa; K.G. Lokugamage; S. MakinoPages: 165 - 192Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): K. Nakagawa, K.G. Lokugamage, S. Makino Coronaviruses have large positive-strand RNA genomes that are 5′ capped and 3′ polyadenylated. The 5′-terminal two-thirds of the genome contain two open reading frames (ORFs), 1a and 1b, that together make up the viral replicase gene and encode two large polyproteins that are processed by viral proteases into 15–16 nonstructural proteins, most of them being involved in viral RNA synthesis. ORFs located in the 3′-terminal one-third of the genome encode structural and accessory proteins and are expressed from a set of 5′ leader-containing subgenomic mRNAs that are synthesized by a process called discontinuous transcription. Coronavirus protein synthesis not only involves cap-dependent translation mechanisms but also employs regulatory mechanisms, such as ribosomal frameshifting. Coronavirus replication is known to affect cellular translation, involving activation of stress-induced signaling pathways, and employing viral proteins that affect cellular mRNA translation and RNA stability. This chapter describes our current understanding of the mechanisms involved in coronavirus mRNA translation and changes in host mRNA translation observed in coronavirus-infected cells.

Authors:G. Tekes; H.-J. ThielPages: 193 - 218Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): G. Tekes, H.-J. Thiel Feline infectious peritonitis (FIP) belongs to the few animal virus diseases in which, in the course of a generally harmless persistent infection, a virus acquires a small number of mutations that fundamentally change its pathogenicity, invariably resulting in a fatal outcome. The causative agent of this deadly disease, feline infectious peritonitis virus (FIPV), arises from feline enteric coronavirus (FECV). The review summarizes our current knowledge of the genome and proteome of feline coronaviruses (FCoVs), focusing on the viral surface (spike) protein S and the five accessory proteins. We also review the current classification of FCoVs into distinct serotypes and biotypes, cellular receptors of FCoVs and their presumed role in viral virulence, and discuss other aspects of FIPV-induced pathogenesis. Our current knowledge of genetic differences between FECVs and FIPVs has been mainly based on comparative sequence analyses that revealed “discriminatory” mutations that are present in FIPVs but not in FECVs. Most of these mutations result in amino acid substitutions in the S protein and these may have a critical role in the switch from FECV to FIPV. In most cases, the precise roles of these mutations in the molecular pathogenesis of FIP have not been tested experimentally in the natural host, mainly due to the lack of suitable experimental tools including genetically engineered virus mutants. We discuss the recent progress in the development of FCoV reverse genetics systems suitable to generate recombinant field viruses containing appropriate mutations for in vivo studies.

Authors:E. Kindler; V. Thiel; F. WeberPages: 219 - 243Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): E. Kindler, V. Thiel, F. Weber Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are the most severe coronavirus (CoV)-associated diseases in humans. The causative agents, SARS-CoV and MERS-CoV, are of zoonotic origin but may be transmitted to humans, causing severe and often fatal respiratory disease in their new host. The two coronaviruses are thought to encode an unusually large number of factors that allow them to thrive and replicate in the presence of efficient host defense mechanisms, especially the antiviral interferon system. Here, we review the recent progress in our understanding of the strategies that highly pathogenic coronaviruses employ to escape, dampen, or block the antiviral interferon response in human cells.

Authors:L. Enjuanes; S. Zuñiga; C. Castaño-Rodriguez; J. Gutierrez-Alvarez; J. Canton; I. SolaPages: 245 - 286Abstract: Publication date: 2016 Source:Advances in Virus Research, Volume 96 Author(s): L. Enjuanes, S. Zuñiga, C. Castaño-Rodriguez, J. Gutierrez-Alvarez, J. Canton, I. Sola Virus vaccines have to be immunogenic, sufficiently stable, safe, and suitable to induce long-lasting immunity. To meet these requirements, vaccine studies need to provide a comprehensive understanding of (i) the protective roles of antiviral B and T-cell-mediated immune responses, (ii) the complexity and plasticity of major viral antigens, and (iii) virus molecular biology and pathogenesis. There are many types of vaccines including subunit vaccines, whole-inactivated virus, vectored, and live-attenuated virus vaccines, each of which featuring specific advantages and limitations. While nonliving virus vaccines have clear advantages in being safe and stable, they may cause side effects and be less efficacious compared to live-attenuated virus vaccines. In most cases, the latter induce long-lasting immunity but they may require special safety measures to prevent reversion to highly virulent viruses following vaccination. The chapter summarizes the recent progress in the development of coronavirus (CoV) vaccines, focusing on two zoonotic CoVs, the severe acute respiratory syndrome CoV (SARS-CoV), and the Middle East respiratory syndrome CoV, both of which cause deadly disease and epidemics in humans. The development of attenuated virus vaccines to combat infections caused by highly pathogenic CoVs was largely based on the identification and characterization of viral virulence proteins that, for example, interfere with the innate and adaptive immune response or are involved in interactions with specific cell types, such as macrophages, dendritic and epithelial cells, and T lymphocytes, thereby modulating antiviral host responses and viral pathogenesis and potentially resulting in deleterious side effects following vaccination.

Authors:Yolanda Revilla; Daniel Pérez-Núñez; Juergen A. RichtAbstract: Publication date: Available online 21 November 2017 Source:Advances in Virus Research Author(s): Yolanda Revilla, Daniel Pérez-Núñez, Juergen A. Richt African swine fever (ASF) is an acute and often fatal disease affecting domestic pigs and wild boar, with severe economic consequences for affected countries. ASF is endemic in sub-Saharan Africa and the island of Sardinia, Italy. Since 2007, the virus emerged in the republic of Georgia, and since then spread throughout the Caucasus region and Russia. Outbreaks have also been reported in Belarus, Ukraine, Lithuania, Latvia, Estonia, Romania, Moldova, Czech Republic, and Poland, threatening neighboring West European countries. The causative agent, the African swine fever virus (ASFV), is a large, enveloped, double-stranded DNA virus that enters the cell by macropinocytosis and a clathrin-dependent mechanism. ASFV is able to interfere with various cellular signaling pathways resulting in immunomodulation, thus making the development of an efficacious vaccine very challenging. Inactivated preparations of ASFV do not confer protection, and the role of antibodies in protection remains unclear. The use of live-attenuated vaccines, although rendering suitable levels of protection, presents difficulties due to safety and side effects in the vaccinated animals. Several ASFV proteins have been reported to induce neutralizing antibodies in immunized pigs, and vaccination strategies based on DNA vaccines and recombinant proteins have also been explored, however, without being very successful. The complexity of the virus particle and the ability of the virus to modulate host immune responses are most likely the reason for this failure. Furthermore, no permanent cell lines able to sustain productive virus infection by both virulent and naturally attenuated ASFV strains exist so far, thus impairing basic research and the commercial production of attenuated vaccine candidates.

Authors:Juan A. Mondotte; Maria-Carla SalehAbstract: Publication date: Available online 21 November 2017 Source:Advances in Virus Research Author(s): Juan A. Mondotte, Maria-Carla Saleh The use of Drosophila as a model organism has made an important contribution to our understanding of the function and regulation of innate immunity in insects. Indeed, insects can discriminate between different types of pathogens and mount specific and effective responses. Strikingly, the same pathogen can trigger a different immune response in the same organism, depending solely on the route of infection by which the pathogen is delivered. In this review, we recapitulate what is known about antiviral responses in Drosophila, and how they are triggered depending on the route and the mode used for the virus to infect its host.

Authors:Rogier Bodewes; Thijs KuikenAbstract: Publication date: Available online 21 November 2017 Source:Advances in Virus Research Author(s): Rogier Bodewes, Thijs Kuiken Waterbirds are the main reservoir for low pathogenic avian influenza A viruses (LPAIV), from which occasional spillover to poultry occurs. When circulating among poultry, LPAIV may become highly pathogenic avian influenza A viruses (HPAIV). In recent years, the epidemiology of HPAIV viruses has changed drastically. HPAIV H5N1 are currently endemic among poultry in a number of countries. In addition, global spread of HPAIV H5Nx viruses has resulted in major outbreaks among wild birds and poultry worldwide. Using data collected during these outbreaks, the role of migratory birds as a vector became increasingly clear. Here we provide an overview of current data about various aspects of the changing role of wild birds in the epidemiology of avian influenza A viruses.

Authors:Bradley I. Hillman; Aulia Annisa; Nobuhiro SuzukiAbstract: Publication date: Available online 21 November 2017 Source:Advances in Virus Research Author(s): Bradley I. Hillman, Aulia Annisa, Nobuhiro Suzuki Plant-associated fungi are infected by viruses at the incidence rates from a few % to over 90%. Multiple viruses often coinfect fungal hosts, and occasionally alter their phenotypes, but most of the infections are asymptomatic. Phenotypic alterations are grouped into two types: harmful or beneficial to the host fungi. Harmful interactions between viruses and hosts include hypovirulence and/or debilitation that are documented in a number of phytopathogenic fungi, exemplified by the chestnut blight, white root rot, and rapeseed rot fungi. Beneficial interactions are observed in a limited number of plant endophytic and pathogenic fungi where heat tolerance and virulence are enhanced, respectively. Coinfections of fungi provided a platform for discoveries of interesting virus/virus interactions that include synergistic, as in the case for those in plants, and unique antagonistic and mutualistic interactions between unrelated RNA viruses. Also discussed here are coinfection-induced genome rearrangements and frequently observed coinfections by the simplest positive-strand RNA virus, the mitoviruses.

Authors:Caitlin Milligan; Jennifer A. Slyker; Julie OverbaughAbstract: Publication date: Available online 16 November 2017 Source:Advances in Virus Research Author(s): Caitlin Milligan, Jennifer A. Slyker, Julie Overbaugh HIV mother-to-child transmission (MTCT) represents a success story in the HIV/AIDS field given the significant reduction in number of transmission events with the scale-up of antiretroviral treatment and other prevention methods. Nevertheless, MTCT still occurs and better understanding of the basic biology and immunology of transmission will aid in future prevention and treatment efforts. MTCT is a unique setting given that the transmission pair is known and the infant receives passively transferred HIV-specific antibodies from the mother while in utero. Thus, infant exposure to HIV occurs in the face of HIV-specific antibodies, especially during delivery and breastfeeding. This review highlights the immune correlates of protection in HIV MTCT including humoral (neutralizing antibodies, antibody-dependent cellular cytotoxicity, and binding epitopes), cellular, and innate immune factors. We further discuss the future implications of this research as it pertains to opportunities for passive and active vaccination with the ultimate goal of eliminating HIV MTCT.

Authors:Danica M. Sutherland; Pavithra Aravamudhan; Terence S. DermodyAbstract: Publication date: Available online 13 November 2017 Source:Advances in Virus Research Author(s): Danica M. Sutherland, Pavithra Aravamudhan, Terence S. Dermody Viruses are constantly engaged in a molecular arms race with the host, where efficient and tactical use of cellular receptors benefits critical steps in infection. Receptor use dictates initiation, establishment, and spread of viral infection to new tissues and hosts. Mammalian orthoreoviruses (reoviruses) are pervasive pathogens that use multiple receptors to overcome protective host barriers to disseminate from sites of initial infection and cause disease in young mammals. In particular, reovirus invades the central nervous system (CNS) with serotype-dependent tropism and disease. A single viral gene, encoding the attachment protein σ1, segregates with distinct patterns of CNS injury. Despite the identification and characterization of several reovirus receptors, host factors that dictate tropism via interaction with σ1 remain undefined. Here, we summarize the state of the reovirus receptor field and discuss open questions toward understanding how the reovirus attachment protein dictates CNS tropism.

Authors:Michael M. GoodinAbstract: Publication date: Available online 2 November 2017 Source:Advances in Virus Research Author(s): Michael M. Goodin Protein interaction and localization studies in plants are a fundamental component of achieving mechanistic understanding of virus:plant interactions at the systems level. Many such studies are conducted using transient expression assays in leaves of Nicotiana benthamiana, the most widely used experimental plant host in virology, examined by laser-scanning confocal microscopy. This chapter provides a workflow for protein interaction and localization experiments, with particular attention to the many control and supporting assays that may also need to be performed. Basic principles of microscopy are introduced to aid researchers in the early stages of adding imaging techniques to their experimental repertoire. Three major types of imaging-based experiments are discussed in detail: (i) protein localization using autofluorescent proteins, (ii) colocalization studies, and (iii) bimolecular fluorescence complementation, with emphasis on judicious interpretation of the data obtained from these approaches. In addition to establishing a general framework for protein localization experiments in plants, the need for proteome-scale localization projects is discussed, with emphasis on nuclear-localized proteins.

Authors:Marc H.V. Van RegenmortelAbstract: Publication date: Available online 2 November 2017 Source:Advances in Virus Research Author(s): Marc H.V. Van Regenmortel Virus classification deals with conceptual species classes that have viruses as their members. A virus species cannot be described but can only be defined by listing certain species-defining properties of its member. However, it is not possible to define a virus species by using a single species-defining property. The new 2013 official definition of virus species is not appropriate because it applies equally to virus genera. A nucleotide motif is a chemical part of a viral genome and is not a species-defining property that could be used for establishing new virus species. A virus classification based solely on nucleotide sequences is a classification of viral genomes and not of viruses. The variable distribution of species-defining properties of a polythetic species class is not itself a single common property of all the members of the class, since this would lead to the paradox that every polythetic class is also a monothetic one.

Authors:Stephan Drewes; Petra Straková; Jan F. Drexler; Jens Jacob; Rainer G. UlrichAbstract: Publication date: Available online 28 September 2017 Source:Advances in Virus Research Author(s): Stephan Drewes, Petra Straková, Jan F. Drexler, Jens Jacob, Rainer G. Ulrich Rodents are distributed throughout the world and interact with humans in many ways. They provide vital ecosystem services, some species are useful models in biomedical research and some are held as pet animals. However, many rodent species can have adverse effects such as damage to crops and stored produce, and they are of health concern because of the transmission of pathogens to humans and livestock. The first rodent viruses were discovered by isolation approaches and resulted in break-through knowledge in immunology, molecular and cell biology, and cancer research. In addition to rodent-specific viruses, rodent-borne viruses are causing a large number of zoonotic diseases. Most prominent examples are reemerging outbreaks of human hemorrhagic fever disease cases caused by arena- and hantaviruses. In addition, rodents are reservoirs for vector-borne pathogens, such as tick-borne encephalitis virus and Borrelia spp., and may carry human pathogenic agents, but likely are not involved in their transmission to human. In our days, next-generation sequencing or high-throughput sequencing (HTS) is revolutionizing the speed of the discovery of novel viruses, but other molecular approaches, such as generic RT-PCR/PCR and rolling circle amplification techniques, contribute significantly to the rapidly ongoing process. However, the current knowledge still represents only the tip of the iceberg, when comparing the known human viruses to those known for rodents, the mammalian taxon with the largest species number. The diagnostic potential of HTS-based metagenomic approaches is illustrated by their use in the discovery and complete genome determination of novel borna- and adenoviruses as causative disease agents in squirrels. In conclusion, HTS, in combination with conventional RT-PCR/PCR-based approaches, resulted in a drastically increased knowledge of the diversity of rodent viruses. Future improvements of the used workflows, including bioinformatics analysis, will further enhance our knowledge and preparedness in case of the emergence of novel viruses. Classical virological and additional molecular approaches are needed for genome annotation and functional characterization of novel viruses, discovered by these technologies, and evaluation of their zoonotic potential.

Authors:Martin Hölzer; Manja MarzAbstract: Publication date: Available online 28 September 2017 Source:Advances in Virus Research Author(s): Martin Hölzer, Manja Marz Computer-assisted technologies of the genomic structure, biological function, and evolution of viruses remain a largely neglected area of research. The attention of bioinformaticians to this challenging field is currently unsatisfying in respect to its medical and biological importance. The power of new genome sequencing technologies, associated with new tools to handle “big data”, provides unprecedented opportunities to address fundamental questions in virology. Here, we present an overview of the current technologies, challenges, and advantages of Next-Generation Sequencing (NGS) in relation to the field of virology. We present how viral sequences can be detected de novo out of current short-read NGS data. Furthermore, we discuss the challenges and applications of viral quasispecies and how secondary structures, commonly shaped by RNA viruses, can be computationally predicted. The phylogenetic analysis of viruses, as another ubiquitous field in virology, forms an essential element of describing viral epidemics and challenges current algorithms. Recently, the first specialized virus-bioinformatic organizations have been established. We need to bring together virologists and bioinformaticians and provide a platform for the implementation of interdisciplinary collaborative projects at local and international scales. Above all, there is an urgent need for dedicated software tools to tackle various challenges in virology.

Authors:Guillaume Belbis; Stéphan Zientara; Emmanuel Bréard; Corinne Sailleau; Grégory Caignard; Damien Vitour; Houssam AttouiAbstract: Publication date: Available online 22 September 2017 Source:Advances in Virus Research Author(s): Guillaume Belbis, Stéphan Zientara, Emmanuel Bréard, Corinne Sailleau, Grégory Caignard, Damien Vitour, Houssam Attoui Bluetongue virus (BTV) is the type species of genus Orbivirus within family Reoviridae. Bluetongue virus is transmitted between its ruminant hosts by the bite of Culicoides spp. midges. Severe BT cases are characterized by symptoms including hemorrhagic fever, particularly in sheep, loss of productivity, and death. To date, 27 BTV serotypes have been documented. These include novel isolates of atypical BTV, which have been almost fully characterized using deep sequencing technologies and do not rely on Culicoides vectors for their transmission among hosts. Due to its high economic impact, BT is an Office International des Epizooties (OIE) listed disease that is strictly controlled in international commercial exchanges. During the 20th century, BTV has been endemic in subtropical regions. In the last 15 years, novel strains of nine “typical” BTV serotypes (1, 2, 4, 6, 8, 9, 11, 14, and 16) invaded Europe, some of which caused disease in naive sheep and unexpectedly in bovine herds (particularly serotype 8). Over the past few years, three novel “atypical” serotypes (25–27) were characterized during sequencing studies of animal samples from Switzerland, Kuwait, and France, respectively. Classical serotype-specific inactivated vaccines, although expensive, were very successful in controlling outbreaks as shown with the northern European BTV-8 outbreak which started in the summer of 2006. Technological jumps in deep sequencing methodologies made rapid full characterizations of BTV genome from isolates/tissues feasible. Next-generation sequencing (NGS) approaches are powerful tools to study the variability of BTV genomes on a fine scale. This paper provides information on how NGS impacted our knowledge of the BTV genome.

Authors:Céline L. Boujon; Michel C. Koch; Torsten SeuberlichAbstract: Publication date: Available online 22 September 2017 Source:Advances in Virus Research Author(s): Céline L. Boujon, Michel C. Koch, Torsten Seuberlich Astroviruses are best known as being one of the leading causes of diarrhea in infants and were first described in this context in 1975. In its first years, astrovirus research was mainly restricted to electron microscopy and serology studies. The ability to culture some of these viruses in vitro allowed a first consequent step forward, especially at the molecular level. Since the emergence of more powerful genetic methods, though, the face of this research field has dramatically changed and evolved. From the exponential number of discoveries of new astrovirus strains in the most varied of animal species to their association with atypical diseases, these viruses revealed a lot of surprises, and many more are probably still waiting to be uncovered. This chapter summarizes the most important knowledge about astroviruses and discusses the implication of the latest findings in this area of research.

Authors:Dirk Höper; Claudia Wylezich; Martin BeerAbstract: Publication date: Available online 21 September 2017 Source:Advances in Virus Research Author(s): Dirk Höper, Claudia Wylezich, Martin Beer A new world of possibilities for “virus discovery” was opened up with high-throughput sequencing becoming available in the last decade. While scientifically metagenomic analysis was established before the start of the era of high-throughput sequencing, the availability of the first second-generation sequencers was the kick-off for diagnosticians to use sequencing for the detection of novel pathogens. Today, diagnostic metagenomics is becoming the standard procedure for the detection and genetic characterization of new viruses or novel virus variants. Here, we provide an overview about technical considerations of high-throughput sequencing-based diagnostic metagenomics together with selected examples of “virus discovery” for animal diseases or zoonoses and metagenomics for food safety or basic veterinary research.

Authors:Thomas MettenleiterAbstract: Publication date: Available online 9 September 2017 Source:Advances in Virus Research Author(s): Thomas C. Mettenleiter The history of virology is a history of conceptual and technological inventions and breakthroughs. The development of filters made of porcelain or kieselgur by the end of the 19th century which withheld bacteria allowed the identification of infectious agents smaller than bacteria and noncultivable on the media known at that time and used to grow bacteria. Even finer-grain filters resulted in the observation that the ultravisible novel infectious agents are in fact of particulate nature. Infections of plants and animals were the first to be attributed to these tiny entities. Proof resulted from experimental infection of the natural hosts (including humans). Thus, of the first 30 viruses identified, 20 are veterinary viruses, i.e. infectious agents of poultry and livestock. The discovery that bacteria also have viruses in the 1910s expanded the viral universe which continues today. Filterability and ultravisibility remained a hallmark for the identification of viruses until the advent of the electron microscope in the late 1930s marking another technological breakthrough in virology. Cell culture techniques allowed virus propagation outside the infected organism. In the past decades, the advent and development of molecular biology has brought more innovations culminating in the rapid and accurate determination of genomic material of a variety of living beings including viruses in a hitherto unknown speed and depth using next-generation sequencing and metagenomic analyses. Thus, it is no surprise that new viruses are detected constantly including specimens of unprecedented size and shape. Virologists agree that the viral universe is immense, and only a small fraction has been explored yet.

Authors:Elisa Eggerbauer; Cécile Troupin; Karsten Passior; Florian Pfaff; Dirk Höper; Antonie Neubauer-Juric; Stephanie Haberl; Christiane Bouchier; Thomas C. Mettenleiter; Hervé Bourhy; Thomas Müller; Laurent Dacheux; Conrad M. FreulingAbstract: Publication date: Available online 9 September 2017 Source:Advances in Virus Research Author(s): Elisa Eggerbauer, Cécile Troupin, Karsten Passior, Florian Pfaff, Dirk Höper, Antonie Neubauer-Juric, Stephanie Haberl, Christiane Bouchier, Thomas C. Mettenleiter, Hervé Bourhy, Thomas Müller, Laurent Dacheux, Conrad M. Freuling In 2010, a novel lyssavirus named Bokeloh bat lyssavirus (BBLV) was isolated from a Natterer's bat (Myotis nattereri) in Germany. Two further viruses were isolated in the same country and in France in recent years, all from the same bat species and all found in moribund or dead bats. Here we report the description and the full-length genome sequence of five additional BBLV isolates from Germany (n =4) and France (n =1). Interestingly, all of them were isolated from the Natterer's bat, except one from Germany, which was found in a common Pipistrelle bat (Pipistrellus pipistrellus), a widespread and abundant bat species in Europe. The latter represents the first case of transmission of BBLV to another bat species. Phylogenetic analysis clearly demonstrated the presence of two different lineages among this lyssavirus species: lineages A and B. The spatial distribution of these two lineages remains puzzling, as both of them comprised isolates from France and Germany; although clustering of isolates was observed on a regional scale, especially in Germany. Phylogenetic analysis based on the mitochondrial cytochrome b (CYTB) gene from positive Natterer's bat did not suggest a circulation of the respective BBLV sublineages in specific Natterer's bat subspecies, as all of them were shown to belong to the M. nattereri sensu stricto clade/subspecies and were closely related (German and French positive bats). At the bat host level, we demonstrated that the distribution of BBLV at the late stage of the disease seems large and massive, as viral RNA was detected in many different organs.

Authors:Sandra Blome; Martin Beer; Kerstin WernikeAbstract: Publication date: Available online 9 September 2017 Source:Advances in Virus Research Author(s): Sandra Blome, Martin Beer, Kerstin Wernike Pestiviruses are a group of viruses of veterinary importance infecting livestock animals like pigs, cattle, and sheep, and also wildlife animals like wild boar and different deer species. While for decades only four classical species (Classical swine fever virus, Bovine viral diarrhea virus types 1 and 2, Border disease virus), and a few so-called atypical pestiviruses were known (e.g., Giraffe virus, Pronghorn virus, HoBi virus), a series of novel pestiviruses was identified in the last years (Bungowannah virus, Bat pestivirus, Norway rat pestivirus, Atypical porcine pestivirus, LINDA virus). The Australian Bungowannah virus could be isolated and further characterized by classical sequencing, but all the other latest novel pestiviruses were identified by metagenomics using next-generation sequencing technologies. Here, we describe these new viruses and their discovery and characterization. Differentiation is made between the occurrence of classical pestiviruses in new species and novel viruses or virus types.

Authors:Pablo Guardado-Calvo; Félix A. ReyAbstract: Publication date: Available online 8 April 2017 Source:Advances in Virus Research Author(s): Pablo Guardado-Calvo, Félix A. Rey The Bunyavirales Order encompasses nine families of enveloped viruses containing a single-stranded negative-sense RNA genome divided into three segments. The small (S) and large (L) segments encode proteins participating in genome replication in the infected cell cytoplasm. The middle (M) segment encodes the viral glycoproteins Gn and Gc, which are derived from a precursor polyprotein by host cell proteases. Entry studies are available only for a few viruses in the Order, and in each case they were shown to enter cells via receptor-mediated endocytosis. The acidic endosomal pH triggers the fusion of the viral envelope with the membrane of an endosome. Structural studies on two members of this Order, the phleboviruses and the hantaviruses, have shown that the membrane fusion protein Gc displays a class II fusion protein fold and is homologous to its counterparts in flaviviruses and alphaviruses, which are positive-sense, single-stranded RNA viruses. We analyze here recent data on the structure and function of the structure of the phlebovirus Gc and hantavirus Gn and Gc glycoproteins, and extrapolate common features identified in the amino acid sequences to understand also the structure and function of their counterparts in other families of the Bunyavirales Order. Our analysis also identified clear structural homology between the hantavirus Gn and alphavirus E2 glycoproteins, which make a heterodimer with the corresponding fusion proteins Gc and E1, respectively, revealing that not only the fusion protein has been conserved across viral families.

Authors:Marianne Manchester; Anisha AnandAbstract: Publication date: Available online 31 March 2017 Source:Advances in Virus Research Author(s): Marianne Manchester, Anisha Anand Metabolomics is an analytical profiling technique for measuring and comparing large numbers of metabolites present in biological samples. Combining high-throughput analytical chemistry and multivariate data analysis, metabolomics offers a window on metabolic mechanisms. Because they intimately utilize and often rewire host metabolism, viruses are an excellent choice to study by metabolomics techniques. Studies of the effects of viruses on metabolism during replication in vitro and infection in animal models or human subjects have provided novel insights into these networks and provided new targets for therapy and biomarker development. Identifying the common metabolic pathways utilized by viruses has the potential to reveal those that can be targeted by broad-spectrum antiviral and vaccine approaches.

Authors:P.A. Thibault; R.E. Watkinson; A. Moreira-Soto; J.F. Drexler; B. LeeAbstract: Publication date: Available online 2 February 2017 Source:Advances in Virus Research Author(s): P.A. Thibault, R.E. Watkinson, A. Moreira-Soto, J.F. Drexler, B. Lee The risk of spillover of enzootic paramyxoviruses and the susceptibility of recipient human and domestic animal populations are defined by a broad collection of ecological and molecular factors that interact in ways that are not yet fully understood. Nipah and Hendra viruses were the first highly lethal zoonotic paramyxoviruses discovered in modern times, but other paramyxoviruses from multiple genera are present in bats and other reservoirs that have unknown potential to spillover into humans. We outline our current understanding of paramyxovirus reservoir hosts and the ecological factors that may drive spillover, and we explore the molecular barriers to spillover that emergent paramyxoviruses may encounter. By outlining what is known about enzootic paramyxovirus receptor usage, mechanisms of innate immune evasion, and other host-specific interactions, we highlight the breadth of unexplored avenues that may be important in understanding paramyxovirus emergence.